Thiazolylsalicylic acids

ABSTRACT

New salicylic acid compounds, particularly 5-(heterocyclic)salicylic acid derivatives and process for their preparation are claimed. The new 5-(heterocyclic)salicylic acid compounds described have anti-inflammatory, anti-pyretic and analgesic activity.

United States Patent Sarett et al.

[ 51 July 11,1972

THIAZOLYLSALICYLIC ACIDS Lewis B. Sarett, Skillman; William V. Ruyle, Scotch Plains, both of NJ.

Assignee: Merck & Co., Inc., Rahway, NJ. Filed: June 9, 1970 Appl. No.: 44,866

Inventors:

Related US. Application Data Continuation-impart of Ser. No. 673,273, Oct. 6, 1967, Pat. No. 3,558,641.

[1.8. CI ..260/302 R, 260/3 02 D Int. Cl. ...C07d 91/32 Field of Search ..260/302 R Primary Examiner-Alex Mazel Assistant Examiner-R. J. Gallagher Attorney-Michael C. Sudol, Jr., Harry E. Westlake, J r. and 1. Louis Wolk [5 7] ABSTRACT New salicylic acid compounds, particularly 5-(heterocyclic)- salicylic acid derivatives and process for their preparation are claimed. The new 5-(heterocyclic)salicylic acid compounds described have anti-inflammatory, anti-pyretic and analgesic activity.

5 Claims, No Drawings TI-IIAZOLYLSALICYLIC ACIDS CROSS REFERENCES TO RELATED APPLICATIONS This application is a continuation-in-part of our U. S. Application Ser. No. 673,273, filed Oct. 6, 1967 now U.S. Pat. No. 3 ,5 5 8,641

BACKGROUND OF THE INVENTION The development of anti-inflammatory compounds in the past two decades has seen the growth of a great many new drugs. Most of these have been steroids of the l l-oxygenated pregnane series. These, while highly efiective, have the drawback of causing many side effects. There is a need in the market for equally effective compounds of much simpler structure and having less side effects.

SUMMARY OF THE INVENTION This invention relates to new salicylic acid compounds and processes for producing the same, particularly the S-(heterocyclic )-salicylic acid derivatives. These compounds are useful in that they have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. In addition, they have a useful degree of antipyretic and analgesic activity.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to new heterocyclic phenyl compounds and to processes for producing the same. More specifically, it relates to 5-(heterocyclic)-salicylic acid compounds (2-hydroxy-5heterocyclic benzoic acids). Still more specifically, this invention relates to compounds having the following general formula:

R1 COOH 2 @(5 wherein V I H t v is a 6-membered ring structure containing from l-3 hetero atoms or a 5-membered ring structure containing from l-4 hetero atoms. The hetero atoms are either diethyl amino), hydroxy or alkoxy (preferably lower a!- koxy, such as methoxy or ethoxy).

Preferable examples of the 6-membered ring structure containing from l-3 hetero atoms are 2,3 or 4-pyridyl, 2 or 3 pyrazinyl, 2,4 or S-pyrimidyl, 3 or 4 pyridazinyl, s-triazinyl, 3,4 or 6-as-triazinyl (1,2,3-triazinyl, 1,3,5-triazinyl; 1,2,4- triazinyl).

Preferred examples of S-membered heterocyclic ring structures containing from l-4 hetero atoms are:

2,5 or 4-thiazolyl,

3 or 4-( 1,2,5-thiadiazolyl),

2 or 5-( l ,3,4-thiadiazolyl),

3 or 5-( 1,2,4-thiadizolyl).

In all the above structures, the R substituent on the heterocyclic nucleus can be in any available position and may be in one or more positions.

Representative compounds of this invention are as follows:

5-( 2'-thiazolyl )-salicylic acid,

5-(5'-thiazolyl)-salicylic acid,

5-(4'-thiazolyl)-salicylic acid.

We have found that the compounds described above have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. In

addition, some of them have a useful degree of anti-pyretic and analgesic activity. For these purposes, they are normally administered orally in tablets or capsules, the optimum dosage depending on the particular compound being used and the type and severity of the condition being treated. Although the optimum quantities to be used will depend on the compound employed and the particular type of disease treated, oral dose levels of preferred compounds in the range of 50 mg. to 10 g. per day are useful in the control of said conditions, depending on the activity of the specific compound and the reaction sensitivity of the patient.

The compounds of the instant invention are generally prepared by a carboxylation reaction wherein the appropriate starting material is reacted with carbon dioxide, preferably in the presence of potassium carbonate. The reaction is usually carried out in a pressurized vessel at a wide range of temperatures especially from about 50 C. to 200 C., preferably at about 175 C. at 800 p.s.i. initial pressure. The pressure can also vary from atmospheric pressure on up. The reaction is carried out for a sufficient time to consume the stoimetric amount of carbon dioxide. When the reaction is complete, the desired product can be isolated by extraction with water, the water layer then acidified and the precipitated product recrystallized.

Various methods for preparing the end products are shown in the following examples. The following examples should be construed as illustrations of the invention and not limitations thereof.

EXAMPLE 1 Preparation of 2-hydroxy-5-( 2-thiazoly)-benzoic acid A mixture of 4 g. of 2-(p-hydroxyphenyl)-thiazole and 10 g. of anhydrous potassium carbonate are heated at 200 C. for 6 hours under carbon dioxide gas at an initial pressure of 800 p.s.i. After cooling and venting, the contents of the bomb are taken up in 200 ml. of water and filtered. The filtrate is carefully treated with dilute hydrochloric acid until pH is 7.5. Upon filtration, the filtrate is acidified and the precipitate collected by filtration to yield 2-hydroxy-5-(2-thiazolyl)-benzoic acid.

EXAMPLE 2 5-[4-(2-Chlorothiazolyl)]-salicylic acid A. Preparation of p-(2'-chloro-4-thiazolyl)phenol Boron tribromide was added slowly to a suspension of 2-Cl- 4(p-methoxyphenyl)thiazole in methylene chloride cooled in an ice bath. The reaction mixture was allowed to stand and stir at room temperature for 5 hours. Water was added cautiously and a solid was filtered. It was heated in a saturated NaI-ICO on the steam bath for an hour and the neutral phenol was collected. Preparation of the starting material of the above example is shown in J. Indian Chem. Soc. 32, 427-30 I955).

B. 5-[4-( 2-Chlorothiazolyl) ]-salicylic acid The p-(2-chloro-4-thiazoly])phenol prepared as in Part A above is heated at 225 C. for 8 hours under 4,500 p.s.i. carbon dioxide gas pressure. After the carbon dioxide uptake ceases the contents of the bomb are collected and taken up in ml. of water and filtered. The filtrate was acidified and the crude collected. The salicylic acid was separated from unreacted phenol and a polymeric side product by dissolving it in bicarbonate and acidifying.

EXAMPLE 3 5-(5-Thiazolyl)-salicylic acid A. p-Methoxy-a-thioformamino acetophenone A solution of 8.08 p-methoxyaminoacetophenone hydrochloride prepared as shown in Ber. 20, 2194, (l887) in 30 ml. B 0 is added dropwise and slowly to a well-stirred solution of 44 g. of potassium dithioformate mixture prepared as shown in J. Pharm. Soc. Japan, 71, 869-71, (1951) diluted with 40 ml. H O. A solid immediately appears. The reaction mixture is allowed to stand for 1 hour after the addition and the solid is filtered.

B. -(p-Methoxyphenyl)thiazole 3.0 G. of p-methoxy-a-thioformamino acetophenone is added in portions to 9 ml. concentrated H 50 The reaction mixture becomes hot and turns dark red. After stirring for one-half hour, it is poured into 50 ml. H O. It is filtered and the filtrate is neutralized with NH Ol-l. The precipitate is filtered.

C. 5-(p-Hydroxyphenyl)thiazole 1.6 G. of S-(p-methoxyphenyl)thiazole was combined with 8 ml. of concentrated hydrobromic acid and refluxed for 5 hours. The reaction mixture was cooled and neutralized and the 5-(p-hydroxyphenyl)thiazole was precipitated and collected.

D. 5-(5-Thiazolyl)-salicylic acid The 5-(p-hydroxyphenyl)thiazole prepared in Part C above was heated at 200 C. for 4 hours and then 250 for 4 hours under approximately 800 p.s.i. initial carbon dioxide pressure. After the uptake of the carbon dioxide ceases, the product was worked up in a manner similar to Examples 1 and 2 to yield 5- (5-thiazolyl)-salicylic acid.

EXAMPLE 4 5-(4-Thiazolyl)-salicylic acid A. 4-(p-Methoxyphenyl)thiazole 34 G. of p-methoxyphenacyl bromide, 9.9 g. of phosphorous pentasulfide, 9.8 g. of formamide and 3 drops of piperidine were placed in a round bottom flask and heated on a steam bath until an initial vigorous reaction took place. The reaction mixture was cooled in an ice bath until the reaction subsided and then heated on the steam bath for an additional 5 minutes. After cooling, the reaction material was basified with 200 ml. of 2 N sodium bisulfite solution. The product was extractcd with methyl chloride, dried over magnesium sulfate and concentrated to yield 20 g. of 4-(p-methoxyphenyl )thiazole as a black oil.

B. 4-(p-Hydroxyphenyl)thiazole The crude black oil from Part A was combined with 50 ml. of concentrated hydrobromic acid and refluxed for 3 hours. The reaction mixture was diluted with water and filtered hot to remove the tars. The filtrate was neutralized with ammonium hydroxide and let stand overnight at which time the oil layer solidified and was filtered to yield 0.9 g. of 4-(p-hydroxyphenyl)thiazole.

C. 5-(4-Thiazolyl)-salicylic acid A mixture of 4-(p-hydroxyphenyl)thiazole was added to a hydrogenation bomb and heated at 200 C. under an initial pressure of 725 p.s.i. carbon dioxide gas. After the uptake of carbon dioxide gas the reaction bomb is cooled and the contents isolated in a manner similar to Examples 1 and 2 to yield 5-(4-thiaZolyl)-salicylic acid.

What is claimed is:

l. A compound of the formula:

W I. R, C )OII T' I Het+ wherea: J

1 lS selected from the group consisting of 2.5 or 4- i thiazolyl;

lOlO-H (149 l 

2. 5-(2-Thiazolyl)salicylic acid.
 3. 5-(5-Thiazolyl)salicylic acid.
 4. 5-(4-Thiazolyl)salicylic acid.
 5. 5-(4-(2-Chlorothiazolyl))salicylic acid. 